title: Chemical, biochemical and pharmacological activity of the novel sterically hindered platinum co-ordination complex, cis-[amminedichloro(2-methylpyridine)] platinum(II) (AMD473).
abstract: cis-[Amminedichloro(2-methylpyridine)] platinum(II) (AMD473) is a novel sterically hindered anti-tumour compound designed to circumvent platinum drug resistance and is due to begin clinical trials in 1997. This paper reports the rationale behind the development of AMD473 with regard to its chemical and DNA binding properties. AMD473 circumvents resistance in vitro in acquired cisplatin resistant human ovarian carcinoma (HOC) cell line models (2 h SRB assay mean resistance factor = 2.8 +/- 1.2 microM for AMD473, versus 6.5 +/- 3.5 microM for cisplatin). AMD473 was chosen from a panel of sterically hindered 'pyridine platinum complexes' due to its reduced reactivity with sulphur ligands, unique DNA binding properties and ability to circumvent several of the major resistance mechanisms that manifest in cisplatin-resistant tumour cell lines. AMD473 hydrolyses more slowly (aquation rate = 1.47 +/- 0.32 x 10(-5) s-1 for AMD473 versus 2.98 +/- 0.6 x 10(-5) s-1 for cisplatin) in water than cisplatin and is also shown to have a reduced preference for reaction with soft nucleophiles such as sulphur ligands. Although AMD473 has similar DNA sequence specificity to cisplatin in DNA extracted from drug-treated tumour cells, several adducts unique to AMD473 were formed on naked plasmid DNA. AMD473 was shown to form DNA interstrand cross-links (ICLs) in both naked pBR322 plasmid and SKOV-3 cellular DNA, although AMD473 formed ICLs at a much slower rate than cisplatin. As steric hindrance was increased from AMD494 (unsubstituted pyridine) through AMD473 to AMD508 (2,6-dimethylpyridine), by addition of methyl groups on the pyridine ligand, cross-link formation rates became slower. By alkaline elution, at equimolar doses, AMD473 ICL formation after 24 h incubation was less than that of cisplatin after 4 h. Understanding the chemical and biochemical properties of these sterically hindered platinum complexes may aid the development of more novel platinum chemotherapeutic agents capable of further improving anti-tumour activity in resistant tumours.
authors.affiliation: CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: J
authors.initials: J
authors.lastname: Holford
authors.forename: F
authors.initials: F
authors.lastname: Raynaud
authors.forename: B A
authors.initials: BA
authors.lastname: Murrer
authors.forename: K
authors.initials: K
authors.lastname: Grimaldi
authors.forename: J A
authors.initials: JA
authors.lastname: Hartley
authors.forename: M
authors.initials: M
authors.lastname: Abrams
authors.forename: L R
authors.initials: LR
authors.lastname: Kelland
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009038:Motion; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014867:Water / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; C110525:amminedichloro(2-methylpyridine)platinum(II); D014867:Water; D004247:DNA